Case Report Journal of Gastroenterology, and Endoscopy Published: 15 May, 2017

Rotor Syndrome: An Important Diagnosis to Make

Hirsh D. Trivedi* and Michelle Lai Center, Beth Israel Deaconess Medical Center, USA

Abstract A heightened awareness of the rare, yet benign, forms of hyperbilirubinemia is essential when dealing with hepatobiliary disorders. Rotor syndrome, as well as Dubin-Johnson syndrome, can be mistaken for more severe forms of hepatobiliary disease, which can lead to unnecessary and invasive therapeutic interventions with potential risk of complications. We herein present a case of a patient with Rotor syndrome whose misdiagnosis led to multiple risky interventions. Additionally, we discuss the important diagnostic tools used to identify Rotor syndrome and differentiate it from Dubin-Johnson syndrome.

Introduction Rotor syndrome is a rare, benign and inherited cause of hyperbilirubinemia, which is often misdiagnosed as a more severe form of hepatobiliary disease. The identification of Rotor syndrome is essential in order to prevent misdiagnosis, which can lead to unnecessary investigations and treatment placing the patient at an unwarranted risk of complications. We herein present a case of a 35-year-old male with multiple hospitalizations for “recurrent cholangitis” and repeated interventions with endoscopic retrograde cholangiopancreatography (ERCP) who was ultimately diagnosed with Rotor syndrome. Case Presentation A 35-year-old nonverbal male with a history of traumatic brain injury resulting from a motor vehicle accident eleven years ago presents to the hepatology clinic for evaluation of persistently elevated serum levels. He initially presented to the hospital one and a half years ago with nausea, vomiting, fevers and hypotension consistent with septic shock. He had an elevated total bilirubin level of 3.8 mg/dL (64.98 μmol/L) with a direct bilirubin of 2.6 mg/dL (44.46 μmol/L, 68% of total bilirubin), with normal aspartate aminotransferase (AST), alanine aminotransferase (ALT) OPEN ACCESS and (ALP) levels. He was diagnosed with acute cholangitis in the setting of his *Correspondence: fevers and elevated bilirubin levels and was treated with intravenous antibiotics. He was immediately Hirsh D Trivedi, Liver Center, Beth taken for ERCP, which showed multiple gallstones in the , a common diameter Israel Deaconess Medical Center, 110 of 5mm, no biliary strictures and no filling defects on cholangiogram. A biliary sphincterotomy with Francis Street, 8th floor, Boston, MA balloon sweep was done without any biliary stones to be removed. The patient improved clinically 02215, USA, Tel: 617-632-1070, Fax: on antibiotics with resolution of his fevers and hypotension, but his serum bilirubin remained elevated. Despite the persistent hyperbilirubinemia, he was discharged to a rehabilitation center. 617-632-1065; He re-presented with the same symptoms five months later and was found to have an infiltrate on E-mail: [email protected] chest X-ray consistent with pneumonia and a persistently elevated bilirubin but normal ALT, AST Received Date: 20 Jan 2017 and ALP. He was started on antibiotics for both pneumonia and presumed cholangitis in the setting Accepted Date: 10 May 2017 of elevated bilirubin levels. He underwent emergent placement of a percutaneous cholecystostomy Published Date: 15 May 2017 tube for biliary drainage and was eventually discharged despite persistent hyperbilirubinemia. He Citation: then underwent elective cholecystectomy two months later for known gallstones and developed Trivedi HD, Lai M. Rotor Syndrome: fevers eight days postoperatively. A Computed Tomography (CT) scan was normal without any An Important Diagnosis to Make. J biliary dilation. Another ERCP to rule out biliary leak and cholangitis was normal. Magnetic Gastroenterol Hepatol Endosc. 2017; resonance cholangiopancreatography (MRCP) was pursued and completely normal. Despite the 2(1): 1008. normal MRCP findings, an elective ERCP was pursued one month later due to persistently elevated Copyright © 2017 Hirsh D. Trivedi. This bilirubin levels. An internal biliary stent was placed and removed three months after. His direct is an open access article distributed and total bilirubin levels remained elevated and he was referred to the hepatology clinic for further under the Creative Commons Attribution assessment. At the hepatology clinic, he was hemodynamically stable without any symptoms and License, which permits unrestricted had a benign abdominal examination. A family history was unobtainable since he was nonverbal and use, distribution, and reproduction in resided in a group home. He was not on any hepatotoxic medications. An evaluation for chronic liver disease revealed negative hepatitis serologies, anti-smooth muscle antibody, antinuclear antibody any medium, provided the original work and antimitochondrial antibody as well as normal iron studies, lipase and immunoglobulin levels. is properly cited.

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Table 1: The Features of Rotor syndrome and Dubin-Johnson Syndrome. Characteristics Rotor Syndrome Dubin-Johnson Syndrome Reference Mutation or deletion in SLCO1B1 and SLCO1B3 Mutation in MRP2 (chromosome 10q23-q24) halts Genetic Mechanism Disrupts OATP1B1 or OATP1B3 transporter proteins on [2,6] maturation and causes mislocalization of protein sinusoidal membrane of hepatocytes Defective hepatic storage of conjugated bilirubin and disrupted Deficiency in biliary transport of non-bile acid Pathological Mechanism clearance of drug leading to potential toxicities organic anions Inheritance Autosomal recessive Autosomal recessive Increased total urine coproporphyrin Normal total urine coproporphyrin (80% Urine Coproporphyrin (65% coproporphyrin I) coproporphyrin I) [4] Histology Normal Black liver with dark melanin-like pigment

BSP clearance* Delayed, with 50% reduction No biliary transport

Precipitants OCP, pregnancy, other illness OCP BSP: Bromopthalein Sodium; OCP: Oral Contraceptive Pill *Test is no longer used in a clinical setting

Historic liver enzymes and bilirubin levels were obtained dating or conjugated hyperbilirubinemia. The causes of conjugated back to five years, which showed a chronic elevation in direct and hyperbilirubinemia are mentioned above, where as the differential total bilirubin levels with normal AST, ALT and ALP levels. Given diagnoses for unconjugated hyperbilirubinemia include, but are not his chronically elevated serum bilirubin with completely normal limited to, Gilbert’s syndrome, hemolysis, Crigler-Najjar syndrome, AST, ALT and ALP levels, Rotor or Dubin-Johnson Syndrome was hyperthyroidism and states that impair hepatic bilirubin uptake (i.e. suspected. A urine coproporphyrin excretion analysis exhibited drugs or reduced hepatic perfusion). an elevation in the total urine coproporphyrin level of 195.4 mcg/g Our patient was thought to have septic shock from cholangitis creatinine (reference range: 23.3-32.4 mcg/g creatinine, SI: 297.4 and hyperbilirubinemia. It turned out he was actually having nmol/24 hours) and an elevation in coproporphyrin I level of 171.5 recurrent pneumonias leading to hemodynamic instability in the mcg/g creatinine (reference range: 5.6-28.6 mcg/g creatinine, SI: setting of his congenital benign hyperbilirubinemia. As seen in our 262.4 nmol/24 hours) consistent with a diagnosis of Rotor syndrome. case, this diagnosis is often misdiagnosed as a more severe form of Discussion hepatobiliary disease. A heightened awareness of these diagnoses is essential when treating individuals with hyperbilirubinemia in order Rotor syndrome is a rare, inherited, autosomal recessive to prevent unnecessary interventions and potential complications. disorder, which is benign and asymptomatic [1]. The diagnosis should be considered in any patient who has chronic mild non- References hemolytic hyperbilirubinemia with normal AST, ALT, ALP, and 1. Wolkoff AW, Wolpert E, Pascasio FN, Arias IM. Rotor's syndrome. A gamma-glutamyl transferase (GGT) levels [1]. Rotor syndrome distinct inheritable pathophysiologic entity. Am J Med. 1976;60(2):173-9. occurs due to a defect in the hepatic storage of conjugated bilirubin, 2. van de Steeg E, Stránecký V, Hartmannová H, Nosková L, Hřebíček M, which then leaks into the plasma leading to hyperbilirubinemia [1]. Wagenaar E, et al. Complete OATP1B1 and OATP1B3 deficiency causes Studies have postulated the presence of homozygous mutations human Rotor syndrome by interrupting conjugated bilirubin reuptake of transporter genes on chromosome 12 as the cause of this into the liver. J Clin Invest. 2012;122(2):519-28. condition [2]. Rotor syndrome can be diagnosed by measuring 3. Shimizu Y, Naruto H, Ida S, Kohakura M. Urinary coproporphyrin isomers urinary coproporhyrin excretion, which shows an elevation in the in Rotor's syndrome: a study in eight families. Hepatology. 1981;1(2):173- total urinary coproporphyrin level with 65 percent of the urinary 8. consisting of coproporphyrin I [1-4]. This test not only helps in the diagnosis, but also differentiates it from Dubin-Johnson 4. Strassburg CP. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract Research syndrome, another rare cause of benign hyperbilirubinemia [1,4]. Clin Gastroenterol. 2010;24(5):555-71. Differentiating Rotor syndrome from Dubin-Johnson syndrome is a key step in its diagnostic algorithm. Table 1 describes the 5. Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin differentiating features between Rotor syndrome and Dubin-Johnson transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterol. 2014;146(7):1625-38. syndrome. In Rotor syndrome, HIDA scan shows decreased uptake in the liver with prominent renal excretion [2]. Although liver biopsy 6. Toh S, Wada M, Uchiumi T, Inokuchi A, Makino Y, Horie Y, et al. Genomic is not required in the diagnosis, the absence of dark melanin-like structure of the canalicular multispecific organic anion-transporter gene pigments helps differentiate it from Dubin-Johnson syndrome [5]. (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome. Am J Hum Genet. 1999;64(3):739-46. Both Rotor syndrome and Dubin-Johnson syndrome do not have any specific therapy since they are benign conditions. When considering the differential diagnosis of hyperbilirubinemia syndrome over all, they should be characterized as either unconjugated

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